Acquired immune deficiency syndrome (AIDS) is a fatal disease, reported cases of which have increased dramatically within the past two decades. The virus that causes AIDS was first identified in 1983. It has been known by several names and acronyms. It is the third known T-lymphotropic virus (HTLV-III), and it has the capacity to replicate within cells of the immune system, causing profound cell destruction. The AIDS virus is a retrovirus, a virus that uses reverse transcriptase during replication. This particular retrovirus also has been known as lymphadenopathy-associated virus (LAV), AIDS-related virus (ARV) and, presently, as human immunodeficiency virus (HIV). Two distinct families of HIV have been described to date, namely HIV-1 and HIV-2. The acronym HIV is used herein to refer generically to human immunodeficiency viruses.
HIV exerts profound cytopathic effects on the CD4.sup.+ helper/inducer T-cells, thereby severely compromising the immune system. HIV infection also results in neurological deterioration and, ultimately, in death of infected individuals. Tens of millions of people are infected with HIV worldwide, and, without effective therapy, most of these are doomed to die. During the long latency, the period of time from initial infection to the appearance of symptoms, or death, due to AIDS, infected individuals spread the infection further, by sexual contacts, exchanges of contaminated needles during i.v. drug abuse, transfusions of blood or blood products, or maternal transfer of HIV to a fetus or newborn. Thus, there is not only an urgent need for effective therapeutic agents to inhibit the progression of HIV disease in individuals already infected, but also for methods of prevention of the spread of HIV infection from infected individuals to noninfected individuals. Indeed, the World Health Organization (WHO) has assigned an urgent international priority to the search for an effective anti-HIV prophylactic virucide to help curb the further expansion of the AIDS pandemic (Balter, Science 266, 1312-1313, 1994; Merson, Science 260, 1266-1268, 1993; Taylor, J. NIH Res. 6, 26-27, 1994; Rosenberg et al., Sex. Transm. Dis. 20, 41-44, 1993; Rosenberg, Am. J. Public Health 82, 1473-1478, 1992).
The field of viral therapeutics has developed in response to the need for agents effective against retroviruses, especially HIV. There are many ways in which an agent can exhibit anti-retroviral activity (see, e.g., DeClercq, Adv. Virus Res. 42, 1-55, 1993; DeClercq, J. Acquir. Immun. Def. Synd. 4, 207-218, 1991; Mitsuya et al., Science 249, 1533-1544, 1990). Nucleoside derivatives, such as AZT, which inhibit the viral reverse transcriptase, are among the few clinically active agents that are currently available commercially for anti-HIV therapy. Although very useful in some patients, the utility of AZT and related compounds is limited by toxicity and insufficient therapeutic indices for fully adequate therapy. Also, given more recent revelations of the dynamics of HIV infection (Coffin, Science 267, 483-489, 1995; Cohen, Science 267, 179, 1995; Perelson et al., Science 271, 1582-1586, 1996), it is now increasingly apparent that agents acting as early as possible in the viral replicative cycle are needed to inhibit infection of newly produced, uninfected immune cells generated in the body in response to the virus-induced killing of infected cells. Also, it is essential to neutralize or inhibit new infectious virus produced by infected cells.
Infection of CD4.sup.+ cells by HIV-1 and related primate immunodeficiency viruses begins with interaction of the respective viral envelope glycoproteins (generically termed "gp120") with the cell-surface receptor CD4, followed by fusion and entry (Sattentau, AIDS 2, 101-105, 1988; Koenig et al., PNAS USA 86, 2443-2447, 1989). Productively infected, virus-producing cells express gp120 at the cell surface; interaction of gp120 of infected cells with CD4 on uninfected cells results in formation of dysfunctional multicellular syncytia and further spread of viral infection (Freed et al., Bull. Inst. Pasteur 88, 73, 1990). Thus, the gp120/CD4 interaction is a particularly attractive target for interruption of HIV infection and cytopathogenesis, either by prevention of initial virus-to-cell binding or by blockage of cell-to-cell fusion (Capon et al., Ann. Rev. Immunol. 9, 649-678, 1991). Virus-free or "soluble" gp120 shed from virus or from infected cells in vivo is also an important therapeutic target, since it may otherwise contribute to noninfectious immunopathogenic processes throughout the body, including the central nervous system (Capon et al., 1991, supra; Lipton, Nature 367, 113-114, 1994). Much vaccine research has focused upon gp120; however, progress has been hampered by hypervariability of the gp120-neutralizing determinants and the consequent extreme strain-dependence of viral sensitivity to gp120-directed antibodies (Berzofsky, J. Acq. Immun. Def. Synd. 4, 451-459, 1991). Considerable effort has been devoted to truncated, recombinant "CD4" proteins ("soluble CD4" or "sCD4"), which bind to gp120 and inhibit HIV infectivity in vitro (Capon et al., 1991, supra; Schooley et al., Ann. Int. Med. 112, 247-253, 1990; Husson et al., J. Pediatr. 121, 627-633, 1992). However, clinical isolates, in contrast to laboratory strains of HIV, have proven highly resistant to neutralization by sCD4 (Orloffet al., AIDS Res. Hum. Retrovir. 11, 335-342, 1995; Moore et al., J. Virol. 66, 235-243, 1992). Initial clinical trials of sCD4 (Schooley et al., 1990, supra; Husson et al., 1992, supra), and of sCD4-coupled immunoglobulins (Langner et al., Arch. Virol. 130, 157-170, 1993), and likewise of sCD4-coupled toxins designed to bind and destroy virus-expressing cells (Davey et al., J. Infect. Dis. 170, 1180-1188, 1994; Ramachandran et al., J. Infect. Dis. 170, 1009-1013, 1994), have been disappointing. Newer gene-therapy approaches to generating sCD4 directly in vivo (Morgan et al., AIDS Res. Hum. Retrovir. 10, 1507-1515, 1994) will likely suffer similar frustrations.
The development of a safe and effective vaccine is now considered to be the single most important long-term goal of current research efforts. However, as pointed out by Varmus and Nathanson (Science 280, 1815, 1998), this is a daunting, if not impossible, task. Many past efforts focused on eliciting a neutralizing antibody response against the envelope complex (reviewed in Burton, PNAS USA, 94, 10018-10023, 1997; see, also, Haynes, Lancet, 348, 933-937, 1996). Current strategies for development of an HIV-1 vaccine include live, attenuated virus, inactivated virus combined with an adjuvant, a subunit vaccine, e.g., a recombinant monomeric envelope protein or a peptide, a live vector-based vaccine, and the use of DNA plasmids. However, each approach has its limitations. For example, the use of live, attenuated virus poses the risk of eventual pathogenicity in vaccines. Use of inactivated virus combined with an adjuvant results in anti-cellular, rather than anti-viral, antibodies. The absence of neutralizing antibodies presents a problem for subunit vaccines. In fact, human vaccine trials using monomeric gp120 as an immunogen were disappointing at best (VanCott et al., J. Immunol., 155, 4100-4110, 1995; Haynes, Lancet, 348, 933-937, 1996; Bolognesi et al., Nature, 391, 638-639, 1998; and Connor et al., J. Virol., 72, 1552-1576, 1998). Immunogenicity limits the efficacy of live vector-based vaccines. The use of DNA plasmids is limited by current experience.
Anti-idiotypic antibodies, which carry an internal image of an epitope of an antigen and which are designated as Ab2.beta. antibodies, have been shown to induce protective immunity in animals that intentionally have not been exposed to the native antigen epitope (Poskitt et al., Vaccine, 9, 792-796, 1991; and Greenspan et al., FASEB J., 7, 437-444, 1993). Furthermore, anti-idiotypic antibodies have been shown to have potential for immunotherapy of colorectal cancer and ovarian cancer (Denton et al., Int. J. Cancer, 57, 10-14, 1994; Madiyalakan et al., Hybridoma, 14(2), 199-203 (1995); and Wagner et al., Hybridoma, 16(1), 33-40 (1997)).
Therefore, new antiviral agents, such as anti-idiotypic antibodies, to be used alone or in combination with AZT and/or other available antiviral agents, are needed for effective antiviral therapy against AIDS. New agents, which may be used to prevent HIV infection, also are important for prophylaxis. In both areas of need, the ideal new agents would act as early as possible in the viral life cycle, be as virus-specific as possible (i.e., attack a molecular target specific to the virus but not to the infected or infectible animal host), render the intact virus noninfectious, prevent the death or dysfunction of virus-infected mammalian cells, prevent further production of virus from infected cells, prevent spread of virus infection to uninfected mammalian cells, be highly potent and active against the broadest possible range of strains and isolates of HIV, be resistant to degradation under physiological and rigorous environmental conditions, and be readily and inexpensively produced on a large-scale.
The present invention seeks to provide such antiviral agents as well as methods of using such antiviral agents to prevent or treat a viral infection in an animal. These and other objects and advantages of the present invention, as well as additional inventive features, will become apparent from the description provided herein.